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The biggest debate today in the stem cell world is over how much regulation is needed for new, investigational stem cell therapies that are not as yet approved.

Sometimes it feels very lonely being out there publicly advocating for appropriately thorough regulation of stem cell therapies and at times I get a lot of heat for that, especially from stem cell clinics. For instance, I am publicly opposed to the REGROW Act, a piece of legislation that would dangerously weaken oversight of experimental stem cell therapies. Still, I have not yet seen a statement from major stem cell organizations on these issues. It was therefore a great boost to hear just now that the top stem cell biotech industry organization, The Alliance for Regenerative Medicine (ARM), has issued a statement firmly opposing the REGROW Act.

I want to send kudos to ARM and its more than 250 members.

For years in this debate there was a bright line between the academics as well as mainstream organizations in the stem cell arena (together supporting the need for rigorous science-based stem cell medicine and for the FDA, even if some reforms are needed) versus the dubious stem cell clinics out to make a quick buck and wanting as little regulation as possible.

However, in the past year we’ve seen a troubling seismic shift such that some academics and others who used to support the FDA have begun arguing for dramatically less regulation of experimental stem cell treatments. For more background on these pushes for stem cell deregulation, please see my past posts on the Bipartisan Policy Commission (BPC) report that proposed extreme measures such as conditional approval of experimental stem cell interventions, charging patients to be experimented upon, and eliminating Phase III trials in some cases and also see my post opposing the REGROW Act.

It is a big, positive decision for ARM to oppose the REGROW Act, and I’m encouraged to see that I’m not alone in opposing this overreaching legislation. The reasons for ARM’s opposition and my own rationales for being against the bill substantially overlap. We both focus on the dangers posed to patients by inappropriately extreme deregulation. I can’t speak for ARM, but my impression is that they like many of us support some changes in how stem cell therapies are regulated. Perhaps there is hope that the REGROW Act could reemerge in a new incarnation in the future that is more balanced and would chart a prudent path forward.

I’ve pasted ARM’s statement on the REGROW Act below:

“The Alliance for Regenerative Medicine is appreciative of Senator Kirk’s longtime support of the regenerative medicine sector and his belief in the transformative durable treatments and potential cures this field holds for patients. Our organization is committed to our continued cooperation with Senator Kirk and his staff to advance policies supportive of this sector and expediting potentially life-saving cell therapies, gene therapies and other regenerative medicine products.

However, ARM cannot support the REGROW Act. We continue to believe the proposal does not contain critical statutory protections for patients. We look forward to a continuing dialogue with the sponsors of REGROW Act as well as other stakeholders to create alternative approaches to ensure access to safe and effective regenerative medicine therapies without putting patients at risk, disadvantaging American therapeutic developers and potentially damaging a very promising field of medicine.

Note that ARM leaders Michael Werner and Edward Lanphier seem to be the point people on the REGROW issue.

I believe the regrow act accelerate progress too much for people trying to make money in the field of regenerative medicine. When you have a patented therapy you don’t want someone else to be able to come up with a better therapy before your patent expire..

I bet they like the allogeneic portion of the bill. It is the free for all created by the device side that they probably have a problem with. It will legalize the wild wild west of the existing autologous stem cell market and expand it by providing an FDA stamp of approval. A marketing bonanza. Can you provide a link?

There will be a webcast on April 12, 2016. I urge everyone to listen and make up their own mind, please. Lots of opinions are floating around without everyone doing proper research on what the new policy would actually mean.
Please research how Japan is getting MSCs to patients faster now, for instance for steroid-refractory GvHD (MSCs= the patient’s only chance at life in that instance). This act is very similar to what they are doing in Japan.
I have only seen those in the Pharma sector opposing it so far. Those of us who work daily with MSCs and with Patients who need treatments support it. I assure you I am not after “profits”, as a translational research scientist.
Here is the link to the webcast, please listen:http://bipartisanpolicy.org/events/policy-framework-for-regenerative-cell-therapy/

Hi Jan,
Thank you very much for weighing in on this important discussion. I value having a robust debate on the issues that includes diverse viewpoints. While I disagree with the BPC report and cannot support the REGROW Act, I respect the fact that others including you feel differently. One mission for my blog is to provide a forum for healthy dialogue between many different stakeholders and interested parties, even if (and perhaps especially so) some of them disagree with me.
Best,
Paul

One of my concerns about the BPC report has been that it did not adequately discuss the likely risks associated with the regulatory reforms it proposes (e.g. the risks mentioned now by ARM) so this makes me somewhat concerned that the upcoming Bipartisan Policy forum tomorrow may similarly not present both sides and encourage diverse view points. I hope I’m wrong on the forum. I’ll be curious to see how it goes.

If I understand correctly, there the government is generally paying for the experimental regenerative medicine therapies, but here in the U.S. the patients would have that burden barring some dramatic change in coverage.

But I have not seen any indication that American insurers are interested in paying for experimental stem cell (or other) therapies so that leaves in the proposed model the reality that patients, their families, communities, churches, etc. must to try to raise the often very large sums of money.

Since these therapies are experiments, many are ultimately not going to be effective, so is it fair that the patients paid for them? What if the therapies have unexpected side effects, which is possible since they are again experimental?

There’s got to be a better way than the status quo of today, but there’s also got to be a better way than what BPC/REGROW are proposing, which I believe poses serious risks to both patients and the stem cell field. Where’s the regulatory sweet spot?

Since people would travel around the world to get stem cell therapies anyway, wouldn’t make more sense to let them get stem cell therapies in the US where things can be monitored better than in any other country and data can be collected in the interest of science? If a therapy does not work, collecting data properly, would make it clear very soon! While if we let people go around the world the scams will never end.

I agree with Jan on this one. Paul, your paternalism towards patients is distressing. A lot of patients with life threatening conditions don’t need protection, they need access to products that offer hope and the possibility of relief. If one looks at the conditions in the Act, they include the requirement for adult cells, cells tested for immunogenicity, preliminary clinical efficacy of safety, some efficacy signals, not gene modified, minimally manipulated for non-homologous use or more than minimally manipulated for homologous or non-homologous use etc..this isn’t cowboy stuff here. ART for HIV never went through a placebo controlled trial before it exploded on the scene in late 1996. This law may not be perfect, but it’s a good starting point and new pathways need to be developed at FDA for regenerative medicine. AIDS activists found a constipated agency and pushed it to serve patients. Why such hoopla for ARM’s timidity?

Hi Jeff,
Thanks for your comment.
I believe there needs to be a balance between both protections and access when it comes to still experimental stem cell therapies.

At present the way the FDA is regulating this arena is in my view not working that great and I’ve advocated for specific FDA reforms (e.g. in my stem cell book) to increase transparency and access, but in my opinion the Regrow Act is far too extreme.

For example, I’m not convinced that conditional approval is a net positive for patients. It would only help patients if the therapies turn out to be proven rigorously to be both safe and effective, but since these are still experimental therapies we cannot know the profile of any given therapy until later when the data is produced and analyzed. Getting either ineffective or unsafe therapies to patients quicker doesn’t help those patients. Without data, then faster = riskier.

Regrow seems founded on the dangerous assumption that we already know that these therapies are going to be safe and effective for a particular indication, but we don’t until science proves it.

I also think the requirements of the Act are not so clear or robust for therapies in order to get conditional approval. There would also be potential from Regrow for bad actors to take advantage of the more permissive landscape.

The regulatory experiment in Japan with reduced regen med oversight has just started and could end badly so I’m not sure why so many people point to that as a positive example to emulate. I also do not see any evidence that bypassing Phase III is safe or beneficial.

Both in Japan and in the U.S. with the BPC report (many of its supporters also support Regrow), there is also growing pressure to more widely charge patients for experimental therapies, which to me seems highly questionable and I can’t see how that is good for patients.

I support change in this area overall, but instead of Regrow or what BPC recommends, I am in favor of a more balanced approach that involves faster and simpler FDA triggering of Fast Track, Accelerated or Priority Review or Breakthrough Therapy Designation for cellular and regen med therapies.

As for ARM, I don’t applaud “timidity”, which seems like a pejorative way to describe their stand, but rather their firmness on sticking to a science-based framework that is in the best interests of patients. I’m sure they have their own agenda and I’m a realist, but on Regrow I feel they are right.

I think we are also going to see other stem cell leaders and organizations come out against Regrow in the near future. I look forward to continuing the discussion and debate. It seems that we disagree on a number of things related to stem cell regulations here, but having a robust discussion of important issues from diverse perspectives is hopefully something that we can agree upon as valuable.
Best,
Paul

Hi Paul, you cannot argue with a straight face that FDA regulation is not massively pushing up the costs of research. For example, Uniqure, whose gene therapy Glybera has already been approved in the EU asked the FDA to approve the drug in the US, and the FDA turned around and asked for two additional stage 3 studies to be conducted. Uniqure decided that it wasn’t financially worth it, even though they have a treatment that has been proven to work and is already approved in the EU.

This looks suspiciously like bureaucratic arse covering by the FDA. Is the EMA really that lax that they approved a gene therapy when they actually needed two additional stage 3 trials?

The real problem is that no one at the FDA gets fired for saying no.

The public are getting fed up with this, and politicians are responding.

Paul I think what you are missing here is that thousands of patients and decades of work have demonstrated that MSCs are not “dangerous”. After thirty years of researching them (even with gene modification) I have not seen anything that would make me feel that we are “putting patients in danger” by using them. That would be the last thing in the world I would ever want.

This act requires Phase II data, an IND to be filed, and requires the cells to be made GMP. Data is collected during Phase III. In my opinion, this accelerates the entire field and is FAR better than patients going offshore to get something unregulated.

I 100% agree with you. The REGROW ACT requires the sponsor to prepare and submit annual reports and adverse event reports to the Secretary containing all the information required for approved biological products. I believe that if the FDA holds the sponsors to very high safety standards during the conditional approval period, and if the FDA truly monitors any adverse events in the same manner that they currently monitor the adverse events in a phase III clinical trial, then it is my opinion that the increased safety risk of conditional approval can be managed and that the overall benefit of accelerated cellular therapy outweighs the risk.

Hi Jan,
I agree that the overall safety profile for MSCs is very encouraging and you of course know far more about MSCs than I ever will, but I don’t believe we can or should make universal declarations of their (or really any type of stem cell’s) safety regardless of important variables such as the particular patient from which they are derived, the derivation source tissue (fat, marrow, etc) how they might be handled in culture (e.g. possibility of contamination in many ways) and for how many passages, and the expertise and facilities of those working with them. So there can be a lot of variability.

For instance, I have zero doubt that the MSCs from our facility are top notch, but Regrow would apply to pretty much any lab and wouldn’t require a BLA for years, and some of the other labs out there are frankly not so great.

The nature of the specific applications in which the MSCs are used is also going to make a big difference too and this brings in the important issue of homologous use. Non-homologous uses such as taking adipose MSCs and transplanting them into totally different tissues such as lung, CNS, etc. will have higher relative risks. This doesn’t mean that this shouldn’t be researched, but it something that should be kept in mind and discussed with the FDA.

The other big issue here goes beyond safety to efficacy.

I believe that Regrow would likely end up catalyzing the transplantation of cell products into hundreds or thousands of patients where those specific cell products are not ultimately going to be proven effective. Often there will be no clear expectation of efficacy based on actual data even before the clinical use begins, but in the new regulatory paradigm some people would go ahead and use them anyway based more on hope or excitement than data. Past experience shows that more generally even when there is supportive preliminary efficacy data for any given experimental drug product, most often those trials fail anyway and with Regrow the “data hurdle” to do such experiments becomes much lower.

For these reasons Regrow actually isn’t in the best interest of patients even if giving more liberal access to experimental stem cells seems on the surface to be pro-patient, particularly if as is recommended by BPC the patients are actually charged to be allowed access into clinical trials.
Paul

@ Kyle Cetrulo – you say, FDA will monitor adverse events “in the same manner as in a phase III clinical trial”, but how can that work? In phase III the patients’ responses are compared between carefully selected control and treated groups, whereas after conditional approval it will be more like a phase IV monitoring without controls. It will be impossible to assign any side-effect to the treatment under these circumstances, except perhaps rampant cancer or death.

Unfortunately, the current regulatory framework that has not approved a single cellular therapy in the 15 years of its existence will not help the millions of patients that would benefit from stem cell therapy and these patients are forced to choose stem cell therapies that have zero regulation and oversight. The REGROW ACT might not be perfect but I believe it is light years better then the current system.

The Registry that Arnold Caplan wants to create already exists. The registry is called the CIBMTR (the center for international blood and marrow transplant research) and is administered through HRSA (Health Resources Service Administration), under HHS. .

The CIBMTR already has a voluntary reporting system for cellular therapies. There are forms for the infusion and for product characterization. Safety reporting also occurs through this system. If needed, they could create therapy/disease specific outcomes forms too I imagine.

@douglasmacarthur
Caplan describes nothing more than a Phase IV type study of adverse effects after the event, whereas a Phase III tries to identify them before release of product to the mass population.

The difference is identifying safety issues in a controlled way before release or treating patients as lab rats, a privilege they will have to pay for.

There has to be revisions to FDA regulations, but this is going back to the dark ages. As a clinician, I find it outrageous that some unwary patients in need will take barely tested therapies, only to find themselves on Caplan’s list of unexpected adverse events.

But what the heck, they served their purpose, is that’s what your saying?

@Anne Sonnenberg I understand your point. One of the things that I am afraid about is that these patients would end up in some clinics around the world and their adverse effect will not be reported anywhere. That would cause even more patients to do the same thing and we will learn nothing about even more patients having an adverse effect (but maybe also a positive effect). I am not sure you want that.
As a patient I have seen that happen for more than 10 years and it seems the business of “stem cell clinics” that sell unproven therapies is growing. At the end of the day you have to deal with the whole real world (not just with the clinic /state/ country you live in) and deal with it in a practical way which might be different than an ideal way. I have the impression that your approach would in the end harm more people and prevent progress in the field at te same time. Just my opinion.

As one who works in the regenerative medicine industry and long time adult stem cell industry, I’d take a closer look at ARM to see how many of their people work for Big Pharma. Believe you me, when these stem cell treatments and other regenerative technologies hit the shelves, we’ll be seeing a major drop in Big Pharma’s power, especially over the FDA.

@douglasmacarthur
We need to find a solution yes, but the REGROW Act is not it. I’m hearing more and more that folks supporting it really don’t understand the consequences or that the FDA is also moving to revise it’s regulatory course and this should provide a more appropriate solution for patients.

Regarding stem cell tourism, it is very naive to assume that these clinics will disappear because of the REGROW. In fact, they will receive a boost by becoming legalized in a sense – all they need to do is to claim they are doing a follow-up as REGROW requires and the bad press goes away. But who will police that in China, Mexico and so on.

In any case, the bottom line is not the FDA or REGROW but the health insurers – will they pay for therapies that are still “on trial”, albeit post-marketing? The ones I speak to said that their statutes do not oblige them to reimburse costs incurred through such early approvals and they would wait to see if the therapy in question really is safe and effective. They also said that a Phase IV-like database would not provide this evidence as it is not controlled or independent.

So how does anyone on health insurance afford a therapy after REGROW? Stem cell tourism! “Now a REGROW approved therapy at a price you can afford.” Patients will be exposed to higher risks thanks to REGROW!

The REGROW people have not done their homework on so many issues here.

@Anne Sonnenberg I do not expect stem cell clinics will disappear because of the REGROW act. Probably I didn’t explain my point very well, but never mind.
What do you think of the points made by the CEO of CIRM in the presentation posted above by Jan Nolta?

Lively discussion! The common theme is that I believe everyone responding to this post has the patients’ best interest at heart, and that we all agree that changes need to be made.
The current regulatory system is not keeping pace with the MSC field. How to make changes best and most safely is the only thing debated here!
Please see Dr. Randy Mills’ short talk from the recent meeting in DC “Advancing a New Policy Framework for Regenerative Cell Therapy”. He makes outstanding points.

@douglasmacarthur
I found Randal Mills’ presentation very good (as always). He showed the current need for revision and the consequences of inadequately regulated cell therapies.

Somewhat disappointing, and rather shocking, was the lack of understanding and any basic knowledge of clinical testing and of different stem cell practices shown by Andrew Vogt from the Office of Sen. Mark Kirk (First Panel Discussion).

His primary selling point was to strengthen the US position against Europe and Japan – should that really be the yardstick for safe and effective therapeutics?

Vogt clearly stated that approval after phase II plus post-market surveillance will not make for higher risks for patients. That is simply not possible as anyone who knows how Phase II and Phase III testing differs will tell you.

And this really scared me: “If there is an adverse event there is a clear process that there are no liability issues for those who are involved” What? Patients have adverse events but nobody is liable?

When asked if Phase III trials will be required at all the panel answered, “yes, we should require Phase III trials” – and – “in some instances a full Phase III might be necessary” – and – “but it’s post-approval so it’s a Phase IV”

@Anne Sonnenberg if you have found Randal Mills presentation very good our positions are not very distant. I could be wrong, but l had the impression he was not against the Regrow act.
Anyway, do you think the Regrow could be improved and made good enough or you think it should just be adandoned?
In this case what way forward would you suggest considering Randal Mills presentation?
One last point l would consider is that people in some states have the legal option of assisted suicide, so why should not they have the option of taking an experimental therapy at their own risk?

@douglasmacarthur
Yes, many are in favor of regulatory reform – the FDA also – but REGROW is a quick fix without consideration the larger picture and is a political junket for various senators to jump on the proactive health bandwagon. Bad news for patients.

Can REGROW be improved? Only by restricting the potential damage to a compassionate-care type policy for those tested in Phase II – in which case we don’t need it because we already have one.

To maintain high safety standards for the mass markets, for health insurers to accept reimbursement, and for integration of later therapies coming from iPSC technology, etc, we need a rigorous and well planned regulatory policy, and the FDA and its advisory committees are doing that right now.

You ask if patients shouldn’t be allowed to risk being harmed by an experimental therapy if they chose to do so? Of course, but REGROW gives “approval” to such “experimental therapies” and approval sends a message to patients that it has been rigorously tested. REGROW approval would be like subjecting potentially millions of patients to an experimental therapy. As I said before, that will result in many adverse events.

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